Parkinson's disease is a chronic, progressive neurological disorder affecting approximately 20 in every 100,000 people. The disease is typically characterised by resting tremor, muscle rigidity, bradykinesia and postural instability. Although the exact pathological course of Parkinson's disease is unknown, the dopaminergic neurones in the substantia nigra are progressively destroyed which leads to a net decrease in the amount of dopamine in the basal ganglia. Dopamine replacement with levodopa is the current primary therapy for Parkinson's disease.
After a three to five year period of control, 25% of Parkinson's disease sufferers develop “on-off” fluctuations. These are characterised by periods of a few minutes to a few hours during which the patient is able to move and walk easily (“on”), alternating with periods during which the patient experiences severe akinesia (“off”). Many patients also experience other unpleasant “off” period phenomena, such as depression, anxiety, panic, pain, delusions and dystonia, which follow a time-course parallel to the motor stage. The “off” periods may appear several times a day even when anti-parkinsonian drugs are given at the optimum dosage.
Dopamine agonists have been shown to decrease dyskinesias and “on-off” fluctuations when combined with levodopa therapy. Apomorphine is a non-ergot dopamine agonist which has a high affinity for D2, D3 and D4 and lower affinity for D1, and D5 receptors. It has the following structural formula:

Oral doses in excess of 500 mg apomorphine have been shown to produce a dose-dependent improvement in tremor, rigidity, and akinesia but are associated with drug-induced nephrotoxicity. This is thought to be a result of nephrotoxic metabolites produced by the liver, presumably due to extensive first-pass metabolism.
Subcutaneous injections of apomorphine have proved to be effective in the treatment of “on-off” fluctuations in Parkinson's disease within 5 to 15 minutes, and last for 45 to 90 minutes. Trials have shown consistent reversal of “off” period akinesia, a decrease in daily levodopa requirements and consequently a decrease in the amount of “on” period dyskinesias. Advantages over other dopamine agonists include a quick onset of action and lower incidence of psychological complications. For a “rescue therapy” in patients with “on-off” fluctuations, apomorphine also has the advantage over other dopamine agonists that it has a relatively short half-life.
As there is a large inter-subject variation in pharmacokinetics, patients undergo an initial dose titration period at the start of treatment. Nausea and vomiting which may occur as a result of the peripheral dopaminergic action of apomorphine may be controlled by domperidone. Often, patients on long-term apomorphine treatment are able to discontinue or decrease the dose of domperidone without recurrence of these adverse effects.
The widespread application of apomorphine to control “on-off” fluctuations is limited by the necessity for subcutaneous administration. Alternative routes of administration have consequently been investigated. Intranasal apomorphine was shown to be effective in patients with Parkinson's disease but produced transient nasal blockage and burning sensation in two of five patients tested. Rectal administration of apomorphine has been shown to be effective and to have a longer duration of action than subcutaneously administered drug; however, higher doses of the drug are needed because of some first-pass metabolism. Furthermore, the delayed onset of action limits its application as a supplemental dopamine agonist therapy.
Sublingual administration of apomorphine has also been studied. Minimal first-pass metabolism allows for the use of lower doses compared with standard oral administration of apomorphine. In all studies, all patients (who were known to be responsive to subcutaneous apomorphine) fully “switched on”. The mean time to onset of effect was approximately 30 minutes and was comparable between the studies. The mean duration of action was longer following sublingual administration compared to subcutaneous administration. Unpleasant taste and inconsistency of dissolution were noted formulation problems.
The use of apomorphine in treating sexual dysfunction has also been investigated. For instance, the sublingual administration of apomorphine has been found in a clinical study to have a statistically significant effect on erectile dysfunction when compared with placebo (Dula et al Urology 2000; 56: 130-135). According to the literature, apomorphine promotes sexual function and performance because of the effect it exerts on the brain, in particular on the neurological mechanisms underlying sexual arousal. Apomorphine can thus be used to promote or enhance sexual function, treat sexual dysfunction, enhance libido and/or reduce impotence.
For optimal buccal absorption the apomorphine used should ideally be un-ionised at physiological pH. The pKa of apomorphine is 8.9 so, above a pH of about 9, significant amounts of the drug exist as (free base. Thus at pH 3.5 the proportion of apomorphine which is un-ionised is negligible. The proportion of drug which is un-ionised only starts to increase when the pH approaches 7; an alkaline pH yields increasing proportions of un-ionised drug. Thus, for optimal absorption, the drug should be formulated in an alkaline medium.
Apomorphine undergoes rapid spontaneous oxidation. One way to prevent this is to keep solutions of the drug acidified. It is believed that commercially-available apomorphine for injection has a pH of about 3.5. Since this is intended for injection the pH does not influence systemic absorption. However, the nasal spray formulation described above is also an aqueous solution and is also believed to be acidic. This would imply that the formulation is not optimised for nasal absorption and the nasal irritation that has been reported might well derive from the acidic property of the formulation.
Administration of acidic apomorphine formulations into the mouth results in a stimulation of salivation. The excess saliva produced is rich in bicarbonate, which is intended to neutralise the acid and return the mouth to its normal, near neutral, pH. Although the resultant increase in pH should aid the absorption of apomorphine, there is also an increase in the amount of drug swallowed along with the additional volume of saliva. As a result, the amount of drug available for buccal absorption rapidly decreases.